Method of filling degassed drug product into containers and drug product filling device

ABSTRACT

An inventive drug product filling device for filling a liquid drug product into containers is disclosed. The drug filling device includes a drug product preparer configured for preparing the liquid drug product and a filling station configured for filling the liquid drug product into the containers. The filling station is fluidly coupled to the drug product preparer. A degasser is fluidly interposed between the drug product preparer and the filling station. The degasser has a membrane configured for at least partially separating off gas from the liquid drug product. Methods of (i) filling a liquid drug product into containers, (ii) increasing the accuracy of the filling weight of a liquid drug product in a container, (iii) increasing the stability oxygen-sensitive active pharmaceutical ingredient in a liquid drug product, and (iv) reducing polysorbate aggregate formation in a liquid drug product are also disclosed.

RELATED APPLICATIONS

This application is a continuation of PCT/EP2019/070198, filed Jul. 26,2019, which claims priority to EP 18 186 014.9, filed Jul. 27, 2018, theentire disclosures of which are hereby incorporated herein by reference.

BACKGROUND

This disclosure relates to a drug product filling device, a method offilling at least one drug product into containers, a method ofincreasing the accuracy of the filling weight of a liquid drug productin a container, a method of increasing the stability of at least oneoxygen-sensitive active pharmaceutical ingredient in a liquid drugproduct, and to a method of reducing polysorbate aggregate formation ina liquid drug product. The device and methods of this disclosure, as anexample, may be used for filling liquid medical or pharmaceuticalproducts into containers, such as into vials, syringes or ampoules.Other applications comprising the process of bottling a liquid andfurther requiring a removal of one or several gases from the liquid tobe bottled, however, are also feasible.

Liquid solutions may contain gases in dissolved form or as bubbles ormicrobubbles. In many areas dealing with liquids, the removal of gasesfrom the liquids is a common challenge since the presence of bubblesmight interfere with specific processes or requirements, for example inthe quality control the vials may be falsely rejected because bubblesare mistaken as particles during visual inspection. In order to removeor reduce the amount of gases in solutions, different devices andmethods are commonly used. Thus, in order to reduce the amount of CO₂dissolved in water, for example, to produce highly purified water forpharmaceutical purposes, different methods and devices have beenemployed including the use of chemicals such as NaOH which may convertCO₂ into carbonate that may subsequently be removed, e.g., by reverseosmosis. In order to meet the challenge of removing one or several gasesfrom a liquid solution use may also be made of membrane-based modulessuch as Liqui-Cel® membrane contactors. Membrane-based methods anddevices for the removal of gases from liquids are a solution commonlyemployed in a wide range of areas, such as for example in the area ofwater treatment, in chromatography, in the beverage industry, in thecoatings and paint industry as well as in the production of high puritywater for pharmaceutical purposes.

Medical or pharmaceutical products must further comply with a largenumber of safety regulations. Thus, the presence of particles in aliquid drug product must usually be prevented in order to reducepotential risks for the user of such products. Therefore, vials filledwith such products are usually routinely visually inspected for thepresence of particles using fully automated or semi-automated systemssince the presence of particles might constitute a risk for a potentialfuture user. Generally, these systems are often unable to distinguishbetween a particle and a bubble. Thus, the presence of bubbles in thedrug products that are filled in containers may lead to an erroneoussorting out of containers since the bubbles may easily be mistaken forparticles which might constitute a potential danger for a future user.

Drug product filling devices and methods of filling at least one drugproduct into containers which are known in the art usually comprise adegassing step of a bulk solution of the drug product which normallyrelies on the application of a vacuum. Despite the advantages of themethods and devices known in the art, numerous challenges remain to betackled. Thus, after the degassing step the bulk solution is usuallytransferred to a filling device with the aid of gaseous nitrogen whichgenerally causes a renewed input of gases such as nitrogen for example.A gas content in liquid drug products, however, may lead to a lowaccuracy of the filling weight of the liquid drug products contained ina container such as a syringe or a vial. Further, the devices andmethods known in the art are more often than not incomplete andineffective. Furthermore, they are usually time-consuming since theygenerally constitute a separate, non-continuous step that takes place inaddition to the filling process. Additionally, stationary degassing ofthe bulk solution does usually not completely remove dissolved gasespresent in the solution.

SUMMARY

This disclosure teaches a drug product filling device, a method offilling at least one drug product into containers and a method ofincreasing the accuracy of the filling weight of a liquid drug productin a container, which at least partially avoid the drawbacks anddisadvantages of known methods and devices of similar kind known in theart. Specifically, this disclosure teaches increasing the yield ofcontainers filled with the liquid drug product.

As used in the following, the terms “have,” “comprise” or “include” orany arbitrary grammatical variations thereof are used in a non-exclusiveway. Thus, these terms may both refer to a situation in which, besidesthe feature introduced by these terms, no further features are presentin the entity described in this context and to a situation in which oneor more further features are present. As an example, the expressions “Ahas B,” “A comprises B” and “A includes B” may both refer to a situationin which, besides B, no other element is present in A (i.e., a situationin which A solely and exclusively consists of B) and to a situation inwhich, besides B, one or more further elements are present in entity A,such as element C, elements C and D or even further elements.

Further, it shall be noted that the terms “at least one,” “one or more”or similar expressions indicating that a feature or element may bepresent once or more than once typically will be used only once whenintroducing the respective feature or element. In the following, in mostcases, when referring to the respective feature or element, theexpressions “at least one” or “one or more” will not be repeated,non-withstanding the fact that the respective feature or element may bepresent once or more than once. It shall also be understood for purposesof this disclosure and appended claims that, regardless of whether thephrases “one or more” or “at least one” precede an element or featureappearing in this disclosure or claims, such element or feature shallnot receive a singular interpretation unless it is made explicit herein.By way of non-limiting example, the terms “filling station,” “degasser,”“drug product preparer,” and “liquid drug product,” to name just a few,should be interpreted wherever they appear in this disclosure and claimsto mean “at least one” or “one or more” regardless of whether they areintroduced with the expressions “at least one” or “one or more.” Allother terms used herein should be similarly interpreted unless it ismade explicit that a singular interpretation is intended.

Further, as used in the following, the terms “preferably,” “morepreferably,” “particularly,” “more particularly,” “specifically,” “morespecifically” or similar terms are used in conjunction with optionalfeatures, without restricting alternative possibilities. Thus, featuresintroduced by these terms are optional features and are not intended torestrict the scope of the claims in any way. The invention may, as theskilled person will recognize, be performed by using alternativefeatures. Similarly, features introduced by “in an embodiment of theinvention” or similar expressions are intended to be optional features,without any restriction regarding alternative embodiments of theinvention, without any restrictions regarding the scope of the inventionand without any restriction regarding the possibility of combining thefeatures introduced in such way with other optional or non-optionalfeatures of the invention.

In a first aspect of this disclosure, a drug product filling device forfilling at least one drug product into containers is disclosed. The drugproduct filling device comprises at least one drug product preparationdevice, the drug product preparation device being configured forpreparing and/or storing the liquid drug product. The drug productfilling device further comprises at least one filling station forfilling the liquid drug product into the containers, the filling stationbeing fluidically coupled to the drug product preparation device. Thedrug product filling device furthermore comprises at least one degassingdevice, the degassing device being fluidically interposed in between thedrug product preparation device and the filling station and thedegassing device comprising at least one membrane for at least partiallyseparating off at least one gas from the liquid drug product.

The term “drug product” as used herein is a broad term and is to begiven its ordinary and customary meaning to a person of ordinary skillin the art and is not to be limited to a special or customized meaning.The term specifically may refer, without limitation, to a solution, aliquid or a suspension that may be usable as a medication or that may beused or prepared in the process of producing a medication or apreparation or that may be used or prepared as an interstage, aprecursor or a compound of a medication or a preparation. Thus, the drugproduct may for example be used as part of or in connection with atreatment of a disease, a prevention, a prophylaxis or a diagnosticanalysis. The drug product may specifically comprise at least one gas,such as at least one gas that is dissolved in the solution, the liquidor the suspension of the drug product.

The term “filling device” as used herein is a broad term and is to begiven its ordinary and customary meaning to a person of ordinary skillin the art and is not to be limited to a special or customized meaning.The term specifically may refer, without limitation, to a deviceconfigured for dispensing, releasing or conducting an arbitrarysolution, liquid or suspension into receptacles or containers.

The term “container” as used herein is a broad term and is to be givenits ordinary and customary meaning to a person of ordinary skill in theart and is not to be limited to a special or customized meaning. Theterm specifically may refer, without limitation, to an arbitrarycontainer or receptacle configured for holding at least one liquid, suchas, for example, a vial, in particular, a glass vial, a syringe or anampoule.

The term “drug product preparation device” (also referred to herein as“drug product preparer”) as used herein is a broad term and is to begiven its ordinary and customary meaning to a person of ordinary skillin the art and is not to be limited to a special or customized meaning.The term specifically may refer, without limitation, to a deviceconfigured for being used in the process of making, producing,fabricating or storing a drug product. As an example, the drug productpreparation device may comprise at least one of a mixing vessel, areactor, a stirring device or agitator, a storing vessel, a tank, atransport vessel, e.g., a drug product transport container, and/or anyother device suited for being used in the context of drug productpreparation, drug product storage and/or drug product transportation.

The term “filling station” as used herein is a broad term and is to begiven its ordinary and customary meaning to a person of ordinary skillin the art and is not to be limited to a special or customized meaning.The term specifically may refer, without limitation, to a device whichmay be part of the filling device as defined above and which is suitedto fill the at least one drug product into the containers. The fillingstation may be or may comprise at least one liquid handling device whichis configured for filling, dispensing or metering the drug product intothe containers. Thus, as an example, the filling station may comprise atleast one of a dispenser, a nozzle, a valve or the like. The fillingstation may further comprise at least one filling line. The fillingstation may be configured for filling a large number of containers in asequential and/or in a parallel fashion. As an example, the fillingstation may comprise a number of N nozzles or dispensers forsimultaneously filling the drug product into a batch of N containers,followed by a subsequent batch of N containers and so forth.

The term “fluidically coupled” as used herein is a broad term and is tobe given its ordinary and customary meaning to a person of ordinaryskill in the art and is not to be limited to a special or customizedmeaning. In this disclosure, the terms “fluidically” and “fluidly” areused synonymously and interchangeably. The terms “fluidically coupled”and “fluidly coupled” specifically may refer, without limitation, to afirst device and a second device, wherein the first device and thesecond device are connected in such a way that an arbitrary fluid or anarbitrary liquid may be movable or transferable from the first device tothe second device and/or vice versa.

The term “degassing device” (also referred to as a “degasser” herein) asused herein is a broad term and is to be given its ordinary andcustomary meaning to a person of ordinary skill in the art and is not tobe limited to a special or customized meaning. The term specifically mayrefer, without limitation, to a device configured for at least partiallyseparating off at least one gas of a liquid that is conducted throughthe degassing device. Therein, various physical principles may be usedfor separating off the gas. As an example, the degassing device maycomprise, as will be outlined in further detail below, at least onedegassing device based on osmosis. In addition, however, otherprinciples may be used.

The term “fluidically interposed” (or “fluidly interposed”) as usedherein is a broad term and is to be given its ordinary and customarymeaning to a person of ordinary skill in the art and is not to belimited to a special or customized meaning. The term specifically mayrefer, without limitation, to a device being connected to at least onefirst device and at least one second device such that an arbitrary fluidor an arbitrary liquid may be movable or transportable from the firstdevice to the second device via the device that is fluidicallyinterposed in between the first device and the second device.

The term “membrane” as used herein is a broad term and is to be givenits ordinary and customary meaning to a person of ordinary skill in theart and is not to be limited to a special or customized meaning. Theterm specifically may refer, without limitation, to a three-dimensionalobject whose dimension in a first direction of extension falls below thedimension in a second and third direction of extension of the devicesuch that a shape of the object may be described as a layer or assheet-like, wherein the layer or sheet-like object is configured for atleast partially delimiting or delineating a first space or compartmentbordering on the object. Specifically the layer or sheet-like object maybe configured for separating the first space or compartment from asecond space or compartment. Specifically, the dimension in the firstdirection of extension may be referred to as a thickness of themembrane. In particular, the membrane may be configured to delimit ordelineate the first space or compartment in at least one direction ofextension of the first space or compartment. While at least partiallydelimiting or delineating the first space or compartment, the membranemay further at least partially connect the first space or compartment tothe second space or compartment by being selectively permeable at leastunder certain conditions, which may for example comprise a pressuredifference between a pressure in the first space or compartment and apressure in the second space or compartment. The conditions may furthercomprise other parameters such as for example a temperature of themembrane and/or a temperature of the first space or compartment and/or atemperature of the second space or compartment or flow rate through thefirst compartment. While the membrane may be a selectively permeablemembrane that may allow the passage of specific molecules such asgaseous nitrogen or other gas molecules in at least one direction, themembrane may specifically be a non-porous membrane and prevent a mixing,particularly an uncontrolled mixing, of a content of or a substance inthe first space or compartment with a content of or a substance in thesecond space or compartment.

The expression “at least partially separating off at least one gas fromthe liquid drug product” as used herein is a broad term and is to begiven its ordinary and customary meaning to a person of ordinary skillin the art and is not to be limited to a special or customized meaning.The term specifically may refer, without limitation, to at leastpartially removing or conducting away at least one gas from the liquiddrug product such that an amount of gas that may be dissolved in theliquid drug product is reduced.

The degassing device comprises at least one membrane. The membrane maybe a non-porous membrane. In one embodiment, the membrane may compriseat least one of the following materials: polydimethyldioxane (PDMS),cellulose acetate (CA), polysulfone (PS), polyether sulfone (PES),polyacrilonitrile (PAN), polyvinylidiene fluoride (PVDF), poylpropylene(PP), polyethylene (PE), polyvinyl chloride (PVC),polytetrafluoroethylene (PTFE) and silicone. In a preferred embodiment,the membrane comprises silicone. In particular, the membrane may have athickness of 25 μm to 200 μm, preferably 25 μm to 100 μm, morepreferably 40 μm to 70 μm, most preferably of 55 μm. The term“thickness” may in particular refer to the dimension of the membrane inthe direction of extension. The degassing device may particularly beconfigured for applying a pressure difference over the membrane, withthe liquid drug product being in contact with the membrane on a firstside and with an opposing second side of the membrane being exposed to alower pressure than the first side. Thus, the pressure difference may bethe difference between the magnitude of the pressure on the first sideand the magnitude of the pressure on the second side. Specifically, thepressure difference over the membrane may be 0.1 bar to 3.0 bar,preferably 0.6 bar to 1.0 bar, more preferably 0.8 bar. Further, thedegassing device may comprise at least one of a vacuum source or avacuum port for applying a vacuum to the second side. Specifically, thevacuum source may comprise at last one pump, such as a suction pump. Asan example, the pump may comprise at least one positive displacementpump, e.g., one or more of a rotary vane pump, a lobe pump or the like.In particular, an absolute value of the vacuum applied to the secondside may be 0.010 bar to 0.900 bar, preferably, 0.010 bar to 0.020 bar,more preferably 0.015 bar. The term “vacuum” as used herein is a broadterm and is to be given its ordinary and customary meaning to a personof ordinary skill in the art and is not to be limited to a special orcustomized meaning. The term specifically may refer, without limitation,to an underpressure, a low pressure, a partial vacuum or a negativepressure. Thus, a space, chamber or compartment to which the vacuum isapplied may have a lower pressure than another space, chamber orcompartment to which no vacuum is applied. Specifically, the drugproduct, in the degassing device, may have an absolute pressure of 0.1bar to 3.0 bar, preferably 0.6 bar to 1.0 bar, more preferably 0.8 bar.

In particular, the degassing device may comprise at least one hollowfiber membrane module comprising a plurality of hollow fibers, whereinthe hollow fibers are at least partially formed by the membrane. Theterm “hollow fiber” as used herein is a broad term and is to be givenits ordinary and customary meaning to a person of ordinary skill in theart and is not to be limited to a special or customized meaning. Theterm specifically may refer, without limitation, to a tube, a tubule ora capillary that at least partially defines or comprises an interiorspace or lumen. In particular, the interior space or lumen of the hollowfiber may also be referred to as the inside of the hollow fiber.Specifically, the hollow fibers may have an inner diameter and an outerdiameter, wherein the inner diameter may have a value of 50 μm to 800μm, preferably of 150 μm to 250 μm, more preferably a value of 190 μm,and wherein the outer diameter may have a value of 75 μm to 900 μm,preferably of 150 μm to 450 μm, more preferably a value of 300 μm. Inparticular, the thickness of the membrane may be 55 μm, the innerdiameter of the hollow fiber may be 190 μm and the outer diameter of thehollow fiber may be 300 μm. Further, the plurality of hollow fibers ofthe hollow fiber membrane module may comprise a number of 30 hollowfibers to 30000 hollow fibers.

The number of the hollow fibers of the hollow fiber membrane module mayin particular depend on a size of the hollow fiber membrane module, inparticular on an overall membrane area, i.e., on the sum of membraneareas of all hollow fibers in the hollow fiber membrane module, and/oron a cross sectional area of the hollow fiber membrane module, whereinthe cross sectional area may be perpendicular to a main direction ofextension, in particular to a length, of the hollow fiber membranemodule.

As an example, the fiber count per unit membrane area may be in therange of 1.0 to 4.0 fibers/cm², e.g., 1 to 3 fibers/cm², preferably 1 to1.5 fibers/cm², more preferably 1.26 to 1.42 fibers/cm². Additionally oralternatively, the number of hollow fibers, specifically a fiber count,per cross sectional area unit of the hollow fiber membrane module may be20 cm⁻² to 800 cm⁻², such as 40 cm⁻² to 500 cm⁻², e.g., 42 cm⁻² to 483cm⁻².

Furthermore, a length of the hollow fibers may also depend on the sizeof the hollow fiber membrane module, specifically on the length of thehollow fiber membrane module. The hollow fibers may have a length of 10cm to 16 cm, In particular, the degassing device may be or may comprisea PermSelect® Silicone Membrane Module as available from Med Array Inc.,Ann Arbor, Mich. 48108, U.S.A., such as the hollow fiber membrane modulePDMSXA-2500 and/or the hollow fiber membrane module PSMSXA-1.0.

As an example, hollow fiber membrane modules available by MedArray Inc.,Ann Arbor, Mich. 48108, U.S.A., may be used. A summary of exemplaryembodiments of membrane modules available by this supplier and theirproperties is given in Table 1:

TABLE 1 Exemplary embodiments of characteristic properties of exemplaryembodiments of hollow fiber membrane modules. Cross- Fiber Fiber countsectional count per per cross- Hollow fiber Membrane Module Modulemodule membrane sectional membrane Fiber area length diameter area areamodule area module count [cm²] [cm] [cm] [cm²] [cm⁻²] [cm⁻²] PDMSXA-1030 10 10.9 0.95 0.71 3.00 42.32 tiny PDMSXA 1000 1280 1000 16.0 2.866.42 1.28 199.25 PDMSXA 2500 3200 2500 14.0 3.5 9.62 1.28 332.60 PDMSXA7500 9600 7500 14.0 5.4 22.90 1.28 419.17 PDMSXA-1.0 12600 10000 14.06.0 28.27 1.26 445.63 PDMSXA 2.1 30000 21000 14.2 8.9 62.21 1.43 482.23

The hollow fibers may, specifically, form fiber bundles. The term “fiberbundle” as used herein is a broad term and is to be given its ordinaryand customary meaning to a person of ordinary skill in the art and isnot to be limited to a special or customized meaning. The termspecifically may refer, without limitation, to a plurality of fibers,which are combined or held together, for example such that a commonalignment and/or orientation of the fibers is achieved. In particular,the fiber bundles, on both ends, may be embedded in a sealing. Further,ends of the fiber bundles may be connected to connection ports. The term“connection port” as used herein is a broad term and is to be given itsordinary and customary meaning to a person of ordinary skill in the artand is not to be limited to a special or customized meaning. The termspecifically may refer, without limitation, to an arbitrary deviceconfigured for holding or receiving at least one end of at least onefiber bundle in order to directly or indirectly join, affiliate or linkthe end of the fiber bundle to a further element or component. Thehollow fiber membrane module may further comprise at least one housing,the housing having the hollow fibers disposed therein. Furthermore, thehollow fiber membrane module may comprise at least one fiber entry portconnected to a first end of the hollow fibers, at least one fiber exitport connected to a second end of the hollow fibers, and at least onehousing entry port and at least one housing exit port, both the housingentry port and the housing exit port being connected to at least oneinner space inside the housing between the hollow fibers and a wall ofthe housing.

The term “fiber entry port” as used herein is a broad term and is to begiven its ordinary and customary meaning to a person of ordinary skillin the art and is not to be limited to a special or customized meaning.The term specifically may refer, without limitation, to an arbitrarydevice configured for holding or receiving the first end of the fiberbundle in order to directly or indirectly join, affiliate or link thefirst end of the fiber bundle to a further element or component, e.g.,the preparation device, such that a fluid, in particular a gas or aliquid, may be introduced into the fibers via the fiber entry port. Inparticular, in the case of the fluid being a gas, the fiber entry portmay also be used as a fiber exit port. Thus, as described further below,a vacuum may be applied to the inside of the hollow fiber by connectingone or both of the fiber entry port and the fiber exit port to a suctiondevice. The term “fiber exit port” as used herein is a broad term and isto be given its ordinary and customary meaning to a person of ordinaryskill in the art and is not to be limited to a special or customizedmeaning. The term specifically may refer, without limitation, to anarbitrary device configured for holding or receiving the second end ofthe fiber bundle in order to directly or indirectly join, affiliate orlink the first end of the fiber bundle to a further element orcomponent, e.g., the filling station, such that a fluid, in particular agas or a liquid, contained in the hollow fibers of the fiber bundle maybe exported from the hollow fibers via the fiber exit port. Inparticular, the connection port connected to one end of the fiber bundlemay be implemented as the fiber entry port and the connection port atthe other end of the fiber bundle may be implemented as the fiber exitport. Further, the fiber entry port and/or the fiber exit port may alsobe used as the vacuum port.

The term “housing entry port” as used herein is a broad term and is tobe given its ordinary and customary meaning to a person of ordinaryskill in the art and is not to be limited to a special or customizedmeaning. The term specifically may refer, without limitation, to anarbitrary device configured for directly or indirectly joining,affiliating or linking an inner space of the housing to a furtherelement or component, e.g., the preparation device, such that a fluid,in particular a gas or a liquid, may be introduced into the inner spaceof the housing via the fiber entry port. In particular, in the case ofthe fluid being a gas, the housing entry port may also be used as ahousing exit port. Further, the housing entry port and/or the housingexit port may also be used as the vacuum port. Thus, as describedfurther below, a vacuum may be applied to the inner space by connectingone or both of the housing entry port and the housing exit port to asuction device. The term “housing exit port” as used herein is a broadterm and is to be given its ordinary and customary meaning to a personof ordinary skill in the art and is not to be limited to a special orcustomized meaning. The term specifically may refer, without limitation,to an arbitrary device configured for directly or indirectly joining,affiliating or linking the inner space of the housing to a furtherelement or component to a further element or component, e.g., thefilling station, such that a fluid, in particular a gas or a liquid,contained in inner space of the housing may be exported from the innerspace of the housing via the housing exit port.

The hollow fiber membrane module may be fluidically interposed inbetween the drug product preparation device (for example a compoundingarea) and the filling station in a way selected from the groupconsisting of:

-   i) the fiber entry port may be directly or indirectly fluidically    connected to the drug product preparation device, and the fiber exit    port may be directly or indirectly fluidically connected to the    filling station; or-   ii) the housing entry port may be directly or indirectly fluidically    connected to the drug product preparation device, and the housing    exit port may be directly or indirectly fluidically connected to the    filling station.

Particularly, option i) may be selected, wherein one or both of thehousing entry port and the housing exit port may be connected to asuction device such as for example a vacuum pump, specifically forapplying a vacuum to the inner space of the housing. Furthermore, optionii) may be chosen, wherein one or both of the fiber entry port and thefiber exit port may be connected to a suction device, specifically forapplying a vacuum to the inside of the hollow fibers.

The drug product filling device comprises at least one membrane.Specifically, the membrane may comprise at least one material selectedfrom the group consisting of: polydimethylsiloxane (PDMS); celluloseacetate (CA), polysulfone (PS), polyether sulfone (PES),polyacrilonitrile (PAN), polyvinylidiene fluoride (PVDF), poylpropylene(PP), polyethylene (PE), polyvinyl chloride (PVC),polytetrafluoroethylene (PTFE) and silicone, preferably the membranecomprises silicone. Further, the degassing device may have at least oneentry port connected to the drug product preparation device and at leastone exit port connected to the filling station. Furthermore, thedegassing device may be interposed, specifically fluidically interposed,in between the drug product preparation device and the filling stationin an in-line fashion. Thus, the degassing of the liquid drug productmay take place as a step of a series of sequentially performable stepsin the processes of filling the liquid drug product into containers. Thedrug product filling device may further comprise at least one in-linefiltering device fluidically interposed in between the drug productpreparation device and the filling station. In particular, the in-linefiltering device may comprise a sterile filter. The in-line filteringdevice may further comprise a prefilter, specifically a prefilter forreducing a bioburden. Further, the degassing device may be at leastpartially sterilizable. In particular, the degassing device may be atleast partially sterilizable by at least one of the following means:gamma radiation; beta radiation; steam; autoclavation; sterilization inplace, which may also be abbreviated as SIP. Specifically, the membraneof the degassing device may be sterilizable. Further, at least one ofthe following elements which may form part of the degassing device maybe sterilizable: the hollow fibers, the sealing, the connection ports,the housing, the fiber entry port, the fiber exit port, the housingentry port, the housing exit port. Preferably, all elements of thedegassing device may be sterilizable. Further, a sterilization processof the above-mentioned elements may specifically take place as asterilization-in-place. Thus, areas in contact with the drug product maybe sterilizable without substantial disassembly of the drug productpreparation device. The drug product filling device may further compriseat least one transfer system configured for transferring the drugproduct from the drug product preparation device to the filling station.The at least one transfer system may be or may comprise at least onepressure transfer system that has at least one gas supply, the pressuretransfer system being configured for transferring the drug product fromthe drug product preparation device to the filling station by pressure.In particular, the gas supply may supply nitrogen. Additionally oralternatively, the at least one transfer system may be or may compriseat least one pump. Further, the pressure for transferring the drugproduct from the drug product preparation device to the filling stationmay be of 0.8 bar to 1.0 bar. This pressure may in particular be anabsolute pressure.

The drug product filling device comprises the at least one fillingstation. The filling station, in particular the filling line, mayparticularly comprise at least one inspection device for opticallyinspecting the containers after filling with the liquid drug product.The filling station, in particular the filling line, may furthercomprise at least one selection device having at least one controllerfor automatically recognizing defective containers and for automaticallyremoving defective containers. Specifically, the inspection device maycomprise at least one camera and at least one image recognition device.Furthermore the filling station, in particular the filling line, furthermay comprise at least one closing station for closing the containers,for example by at least one stopper. The closing station may furthercomprise at least one crimping station for fixation of the stopper bycrimping. Additionally or alternatively other devices for closing thecontainers may be used and applied to the containers by the closingstation such as caps that may in particular comprise or be made ofplastic and/or aluminum, e.g., Plascap® manufactured by Daikyo.Furthermore, the closing station may specifically comprise a sealingstation, e.g., for sealing ampoules.

The drug product filling device comprises the at least one drug productpreparation device. The drug product preparation device may beconfigured for preparing the liquid drug product from at least twocomponents. The drug product preparation device may specificallycomprise at least one mixing vessel for mixing at least two componentsof the drug product. The mixing vessel may comprise at least onestirring device for stirring the drug product. The drug productpreparation device may further comprise at least one storage vessel,wherein the storage vessel may be fluidically connected to the fillingstation. The storage vessel may particularly comprise at least onetempering device for one or both of cooling or heating the drug product.The storage vessel may specifically comprise at least one gas supply forsupplying at least one shielding gas into the storage vessel and forstoring the drug product under the shielding gas. In particular, the gassupply may comprise at least one nitrogen supply.

The at least one drug product that is filled into containers by the drugproduct filling device may have a viscosity of 0.2 mPa s to 30 mPa s,preferably of 1 mPa s to 20 mPa s, more preferably, 1 mPa s to 5 mPa s,most preferably, 1 mPa s to 1.5 mPa s. The at least one membrane of thedrug product filling device may have a contact area for being in contactwith the drug product, wherein a size of the contact area may be of 10cm² to 5 m², preferably of 0.5 m² to 1.5 m², more preferably the size ofthe contact area may be about 1 m². The drug product filling device maybe configured for conducting the drug product through the degassingdevice at a rate of 5 L/h to 150 L/h, preferably of 60 L/h to 100 L/h,more preferably of 70 L/h to 90 L/h. In particular, the drug product mayhave a temperature of 0° C. to 25° C., preferably 0 to 8° C. or 15-25°C.; more preferably 2 to 8° C. or 18° C. to 24° C.

As an example, for the exemplary embodiments of the hollow fibermembrane modules of Table 1 above, the following flow rates given inTable 2 may be used:

TABLE 2 Exemplary flow rates for the embodiments of the hollow fibermembrane modules of Table 1. Flow rate Membrane module [L/min] PDMSXA-10tiny  0.001-0.01 PDMSXA 1000  0.2-1.9 PDMSXA 2500  0.2-1.9 PDMSXA 75000.5-6 PDMSXA-1.0 0.5-6 PDMSXA 2.1 2.75-19

The drug product filling device may further comprise a coupling bowhaving at least one first coupling access and at least one secondcoupling access, wherein the degassing device may be fluidicallyconnectable to the drug product preparation device via the firstcoupling access, wherein the degassing device may be fluidicallyconnectable to the filling station via the second coupling access. Inparticular, the degassing device may be directly or indirectlyfluidically connectable to the drug product preparation device via thefirst coupling access and the degassing device may be directly orindirectly connectable to the filling station via the second couplingaccess. In case of a direct fluidic connection between the degassingdevice and the first coupling access and/or the second coupling accessthe degassing device may be directly attached to the first couplingaccess and/or the second coupling access, respectively. In case of anindirect fluidic connection between the degassing device and the firstcoupling access and/or the second coupling access the degassing devicemay be attached to the first coupling access and/or the second couplingaccess, respectively, via at least one further element, such as a tube,a hose or a pipe. The term “fluidically connectable” as used herein is abroad term and is to be given its ordinary and customary meaning to aperson of ordinary skill in the art and is not to be limited to aspecial or customized meaning. The term specifically may refer, withoutlimitation, to a first device and a second device, wherein the firstdevice and the second device can be connected in such a way that anarbitrary fluid or an arbitrary liquid may be movable or transferablefrom the first device to the second device and/or vice versa. Within thescope of this disclosure, the terms “fluidically connected” and“fluidically coupled” may be used interchangeably.

The coupling bow may further comprise at least one holder for mountingthe degassing device. Additionally or alternatively, the drug productfilling device, in particular the drug product preparation device and/orthe filling station, may comprise the holder for mounting the degassingdevice. In particular the holder may be configured to removably receivethe degassing device.

In a second aspect of this disclosure a method of filling at least onedrug product into containers is disclosed. The method comprises thesteps disclosed in the following. The steps may specifically beperformed in the given order. Still, a different order is possible. Themethod may comprise additional steps which are not mentioned. It isfurther possible to perform one or more of the method steps repeatedly.Further, two or more of the method steps may be performed in a timelyoverlapping fashion or simultaneously.

The method comprises the following steps:

-   A) providing at least one drug product filling device configured for    filling at least one liquid drug product into containers comprising:    -   providing at least one drug product preparation device, the drug        product preparation device being configured for preparing a        liquid drug product;    -   providing at least one filling station for filling the liquid        drug product into the containers, the filling station being        fluidically coupled to the drug product preparation device;    -   providing at least one degassing device being fluidically        interposed in between the drug product preparation device and        the filling station and the degassing device comprising at least        one membrane for separating off at least one gas from the liquid        drug product;-   B) conducting the drug product from the drug product preparation    device to the filling station, wherein the drug product is at least    partially degassed upon passing through the degassing device; and-   C) filling the at least partially degassed drug product into the    containers by means of the filling station.

In particular, step B) of the method may further comprise:

-   -   applying a pressure difference over the membrane using the        degassing device, with the liquid drug product being in contact        with the membrane on a first side and with an opposing second        side of the membrane being exposed to a lower pressure than the        first side.

In particular, the degassing device provided in method step A) may beconfigured for applying the pressure difference over the membrane bycomprising at least one of a vacuum source or a vacuum port for applyinga vacuum to the second side. The degassing device may further compriseat least one hollow fiber membrane module comprising a plurality ofhollow fibers, wherein the hollow fibers are at least partially formedby the membrane. The hollow fibers may form fiber bundles.

Further, step B) may specifically comprise:

-   -   conducting the drug product from the drug product preparation        device to the filling station by at least sectionally using at        least one of: a stream of transport gas and a pump.

In particular, the transport gas may be nitrogen. For a description ofpossible embodiments and definitions of devices used in the method,reference may be made to the embodiments, definitions and descriptionsas described above or as described further below. Specifically, the drugproduct filling device as provided in method step A) may be a drugproduct filling device as described above or as described further below.Still, other embodiments are feasible.

The method may comprise an increasing of the accuracy of the fillingweight of the liquid drug product in the container. The increasing ofthe accuracy of the filling weight of the liquid product in thecontainer may comprise preparing the at least one liquid drug product,degassing the liquid drug product by at least partially separating offat least one gas from the liquid drug product by using a degassingdevice, the degassing device comprising at least one membrane; andfilling the degassed liquid drug product into the container.

The method may further comprise an increasing of the stability of atleast one oxygen-sensitive active pharmaceutical ingredient in theliquid drug product. The increasing of the stability of theoxygen-sensitive active pharmaceutical ingredient in the liquid drugproduct may comprise preparing the at least one liquid drug product, theliquid drug product comprising the at least one oxygen-sensitive activepharmaceutical ingredient. Further, the increasing of the stability ofthe oxygen-sensitive active pharmaceutical ingredient in the liquid drugproduct may comprise degassing the liquid drug product by at leastpartially separating off at least one gas from the liquid drug productby using the degassing device, the degassing device comprising themembrane.

The method may further comprise reducing polysorbate aggregate formationin the liquid drug product. The reducing of the polysorbate aggregateformation in the liquid drug product may comprise preparing the at leastone liquid drug product, the liquid drug product comprising at least oneoxygen-sensitive active pharmaceutical ingredient, specifically aprotein, and at least one polysorbate. Further, the reducing of thepolysorbate aggregate formation in the liquid drug product may comprisedegassing the liquid drug product by at least partially separating offat least one gas from the liquid drug product by using the degassingdevice, the degassing device comprising the membrane.

In a third aspect of this disclosure a method of increasing the accuracyof the filling weight of a liquid drug product in a container, isdisclosed. The method comprises the steps disclosed in the following.The steps may specifically be performed in the given order. Still, adifferent order is possible. The method may comprise additional stepswhich are not mentioned. It is further possible to perform one or moreof the method steps repeatedly. Further, two or more of the method stepsmay be performed in a timely overlapping fashion or simultaneously.

The method comprises the following steps:

-   I. preparing the at least one liquid drug product;-   II. degassing the liquid drug product by at least partially    separating off at least one gas from the liquid drug product by    using a degassing device, the degassing device comprising at least    one membrane;-   III. filling the degassed liquid drug product into the container.

For possible definitions of most of the terms used herein, reference maybe made to the disclosure of the drug product filling device or to themethod of filling at least one drug product into containers as disclosedabove or as disclosed in further detail below.

The term “increasing” as used herein is a broad term and is to be givenits ordinary and customary meaning to a person of ordinary skill in theart and is not to be limited to a special or customized meaning. Theterm specifically may refer, without limitation, to the fact that acharacteristic number or figure characterizing a specific property of anobject or a process is higher when using the method as described, ascompared to using other methods.

Thus, for quantifying the accuracy of the filling weight, the nominalfilling weight of the liquid drug product in the container may becompared with the actual filling weight, thereby generating informationon the deviation, such as generating a standard deviation. The lower thedeviation, the higher the filling weight accuracy may be. By comparingthe deviation of liquid drug products filled in a container by usingconventional methods, specifically methods not containing method stepII. of degassing the liquid drug product, with liquid drug productsfilled by using the method according to this disclosure, the reductionof the deviation and, thus, the increase in filling weight may beverified, specifically if the method, apart from the degassing step, isidentical.

The method of increasing the accuracy of the filling weight of a liquiddrug product in a container may specifically comprise using thedegassing device and/or the drug product filling device as describedabove and/or as described further below.

TABLE 3 Exemplary characteristic properties of containers filled withliquid drug product either by a conventional drug product filling deviceor by exemplary embodiments of the drug product filling device accordingto this disclosure comprising the PDMSXA - 1.0 hollow fiber membranemodule from MedArray, Inc. average rejected containers rejectedcontainers filling due to particle due to bubble weight ± σ detectiondetection conventional 15.394 g ± 43.21% 9.24% drug product 0.113 gfilling device drug product 15.450 g ± 19.17% 6.41% filling device 0.102g according to this disclosure, parameter set 1 drug product 15.450 g ±7.82% 6.16% filling device 0.102 g according to this disclosure,parameter set 2 drug product 15.434 g ± 5.14% 6.15% filling device 0.048g according to this disclosure, parameter set 3 drug product 15.418 g ±6.03% 7.02% filling device 0.038 g according to this disclosure,parameter set 4

Table 3 displays exemplary characteristic properties of containersfilled with liquid drug product either by a conventional drug productfilling device or by exemplary embodiments of the drug product fillingdevice according to this disclosure comprising the PDMSXA—1.0 hollowfiber membrane module from MedArray, Inc. For each condition displayedby a row of Table 3, at least 2900 containers were filled with theliquid drug product. The data displayed is generated by first using aconventional drug product filling device and then modifying theconventional drug product filling device to generate a drug productfilling device according to this disclosure by implementingmodifications such as the use of the degassing device. Parameter set 1and parameter set 2 correspond to the parameters used for theconventional drug product filling device. Since the data are acquired ina temporally sequential manner, considerable amounts of gas or gases maystill be present, e.g., in the drug product filling device duringmeasurements displayed as parameter set 1. A degassing effect thusincreases over time as visible, e.g., in the measurements of parameterset 2 as compared to parameter set 1. Modifications of the drug productfilling device for parameter set 3 comprise a slowing of squeezers ofdosing tubes of the drug product preparation device and may contributeto a further increase of the filling weight accuracy and a furtherdecrease of the number of containers rejected due to particle detection.Modifications of the drug product filling device for parameter set 4comprise the use of tubes with a diameter of 3 mm instead of 5 mm aswell as an increase of ventilation cycles and may further increase thefilling weight accuracy while slightly increasing the number ofcontainers rejected due to particle detection as well as the number ofcontainers rejected due to bubble detection. The standard deviation isdenominated in Table 3 as a.

In a fourth aspect of this disclosure a method of increasing thestability of at least one oxygen-sensitive active pharmaceuticalingredient in a liquid drug product, specifically a liquid drug productin a container, is disclosed. Specifically, the oxygen-sensitive activepharmaceutical ingredient may be or may comprise a protein. The methodcomprises the steps disclosed in the following. The steps mayspecifically be performed in the given order. Still, a different orderis possible. The method may comprise additional steps which are notmentioned. It is further possible to perform one or more of the methodsteps repeatedly. Further, two or more of the method steps may beperformed in a timely overlapping fashion or simultaneously.

The method comprises the following steps:

-   -   α. preparing the at least one liquid drug product, the liquid        drug product comprising at least one oxygen-sensitive active        pharmaceutical ingredient; and    -   β. degassing the liquid drug product by at least partially        separating off at least one gas from the liquid drug product by        using a degassing device, the degassing device comprising at        least one membrane.

For possible definitions of most of the terms used herein, reference maybe made to the disclosure of the drug product filling device or to themethod of filling at least one drug product into containers as disclosedabove or as disclosed in further detail below.

The term “liquid drug product” as used in the context of the method ofincreasing the stability of the oxygen-sensitive active pharmaceuticalingredient, specifically may refer to a liquid product which comprises adrug and a solvent. The drug product comprised in the liquid drugproduct may be an oxygen-sensitive active pharmaceutical ingredient,such as at least one protein or a pharmaceutical ingredient comprisingat least one protein, or may comprise at least one oxygen-sensitiveactive pharmaceutical ingredient, specifically at least one protein.However, the liquid drug product may also comprise a protein for otherpurposes, e.g., as stabilizer or carrier for the drug. The method ofincreasing the stability of the at least one oxygen-sensitive activepharmaceutical ingredient in a liquid drug product may in particularcomprise increasing the stability of the protein that the liquid drugproduct may comprise for the purposes of stabilizing or carrying thedrug. The method of increasing the stability of the at least oneoxygen-sensitive active pharmaceutical ingredient in a liquid drugproduct may also comprise increasing the stability of the protein thatthe liquid drug product may comprise for other purposes.

The term “oxygen-sensitive active pharmaceutical ingredient” as usedherein is a broad term and is to be given its ordinary and customarymeaning to a person of ordinary skill in the art and is not to belimited to a special or customized meaning. The term may specificallyrefer, without limitations, to a component that may form part of a drugproduct and that may contribute to the correct functioning of the drugproduct, e.g., by mediating a medical effect of the drug product, bycontributing to the medical effect of the drug product or by mediatingof contributing to qualities of the drug product that support itscorrect functioning, such as the stability or storability of the drugproduct. The active pharmaceutical ingredient specifically may be proneto oxidation, thereby changing one or more of its chemical nature, itschemical structure or its chemical, physical or biological properties.Additionally or alternatively, the active pharmaceutical ingredient maybe oxygen-sensitive in a sense that one or more of the chemical,physical or biological nature or properties of the active pharmaceuticalingredient are affected by the presence of oxygen.

The term “stability of an oxygen-sensitive active pharmaceuticalingredient” as used herein is a broad term and is to be given itsordinary and customary meaning to a person of ordinary skill in the artand is not to be limited to a special or customized meaning. The termspecifically may refer, without limitation, to the capability of anoxygen-sensitive active pharmaceutical ingredient, such as a protein, tomaintain its structural integrity and/or functional integrity.

The structural integrity of the oxygen-sensitive active pharmaceuticalingredient, such as the protein, may be affected by degradationprocesses, i.e., the oxygen-sensitive active pharmaceutical ingredient,in particular the protein, in its entirety or parts thereof may bedegraded. Such degraded oxygen-sensitive active pharmaceuticalingredient, in particular proteins, are typically characterized by animpairment of the primary structure, e.g., accompanied by a lowermolecular weight. Moreover, typically, degradation products such asshorter proteins or peptides as degradation products may occur.

The structural integrity of an oxygen-sensitive active pharmaceuticalingredient, in particular a protein, may be determined by varioussuitable technologies well known to those skilled in the art. Typically,structural integrity can be determined by analyzing a liquid drugproduct comprising at least one oxygen-sensitive active pharmaceuticalingredient, in particular at least one protein, or a sample thereof byspectroscopic techniques such as mass spectroscopy (MS) or NMRspectroscopy. Moreover, protein separation technologies such as gelelectrophoresis, such as polyacrylamide gel electrophoresis (PAGE) orchromatography, such as size exclusion or molecular sievechromatography, may be applied.

Besides or in addition to structural integrity, the functional integrityof an oxygen-sensitive active pharmaceutical ingredient, in particular aprotein, may be affected as well. Accordingly, an oxygen-sensitiveactive pharmaceutical ingredient, in particular a protein, with impairedfunctional integrity shall be unable to exert its normal biologicalfunction. The functional integrity may be affected by degradationprocesses as well, i.e., degradation of an oxygen-sensitive activepharmaceutical ingredient, in particular a protein will, typically, alsoresult in loss of its function. Moreover, the functional integrity asmeant herein also encompasses other causes which result in an impairmentof the function of an oxygen-sensitive active pharmaceutical ingredient,in particular a protein, e.g., impaired folding as well as impairment ofposttranslational modifications, such as impaired glycosylation,phosphorylation or myristylation. Typically, the quaternary, tertiaryand/or secondary structure of an oxygen-sensitive active pharmaceuticalingredient, in particular a protein, may be impaired in such a case.

There are also various suitable technologies well known to those skilledin the art for determining the functional integrity of anoxygen-sensitive active pharmaceutical ingredient, in particular aprotein. It will be understood that a suitable technique in this contextdepends on the nature of the oxygen-sensitive active pharmaceuticalingredient, in particular the protein. In case of an enzyme, e.g., asuitable technique for determining the functional integrity may be anassay measuring the enzymatic activity. In case of a growth factor,cytokine or other stimulating agent, a suitable technique may be anassay measuring the capability of the compound for stimulating orpreventing a biological response. Further, the immunological propertiesof an oxygen-sensitive active pharmaceutical ingredient, in particular aprotein, may also be determined by immunological techniques such asantibody binding assays or affinity chromatography.

Under “increasing the stability of at least one oxygen-sensitive activepharmaceutical ingredient” it is to be understood that the structuraland/or functional integrity of an oxygen-sensitive active pharmaceuticalingredient, in particular a protein shall, compared to a reference, bemaintained over a prolonged time and/or shall be maintained underinferior conditions for stability of the oxygen-sensitive activepharmaceutical ingredient, in particular the protein, such as, e.g.,heat, acidic or basic pH or under oxidizing or reducing conditions.

The increase in stability of the oxygen-sensitive active pharmaceuticalingredient, such as the protein, due to applying the method of thisdisclosure as referred to herein may be determined by comparing thestability of the oxygen-sensitive active pharmaceutical ingredient, inparticular the protein, i.e., the structural and/or functional integrityof an oxygen-sensitive active pharmaceutical ingredient, in particular aprotein, in a sample of a liquid drug product which has been treated bythe method of this disclosure and the stability of the oxygen-sensitiveactive pharmaceutical ingredient, specifically the protein, of a sampleof a control liquid drug product, e.g., a liquid drug product which hasnot been treated by the method of this disclosure. A successfultreatment will be accompanied by an increase in stability of theoxygen-sensitive active pharmaceutical ingredient, particularly theprotein, in the treated sample versus the control sample. Typically,such a comparison of stability determinations may be done at varioustime points in the future after treatment, e.g., in a time coursemeasurement.

Thanks to the method of this disclosure, stability of theoxygen-sensitive active pharmaceutical ingredients, in particular theproteins, in liquid drug products can be significantly increased whichresults in, e.g., better storage or transport capabilities for theproduct.

The method of increasing the stability of the oxygen-sensitive activepharmaceutical ingredient, specifically the protein, in a liquid drugproduct may comprise using the degassing device and/or the drug productfilling device as described above and/or as described further below.

The method may further comprise the following step:

-   -   γ. filling the degassed liquid drug product into at least one        container.

In a fifth aspect of this disclosure a method of reducing the formationof polysorbate aggregate formation in a liquid drug product,specifically a liquid drug product in a container, is disclosed. Themethod comprises the steps disclosed in the following. The steps mayspecifically be performed in the given order. Still, a different orderis possible. The method may comprise additional steps which are notmentioned. It is further possible to perform one or more of the methodsteps repeatedly. Further, two or more of the method steps may beperformed in a timely overlapping fashion or simultaneously.

The method comprises the following steps:

-   -   X. preparing the at least one liquid drug product, the liquid        drug product comprising at least one oxygen-sensitive active        pharmaceutical ingredient, specifically a protein, and at least        one polysorbate; and    -   Y. degassing the liquid drug product by at least partially        separating off at least one gas from the liquid drug product by        using a degassing device, the degassing device comprising at        least one membrane.

For possible definitions of most of the terms used herein, reference maybe made to the disclosure of the drug product filling device or to themethod of filling at least one drug product into containers as disclosedabove or as disclosed in further detail below.

The term “polysorbate” as used herein is a broad term and is to be givenits ordinary and customary meaning to a person of ordinary skill in theart and is not to be limited to a special or customized meaning. Theterm specifically may refer, without limitation, to a class of non-ionicsurfactants used, typically, as emulsifiers. Polysorbates are derivedfrom ethoxylated sorbitan by esterification with fatty acids.Polysorbates are used, typically, in pharmaceuticals or foodpreparations. Typical examples of polysorbates include but are notlimited to Polysorbate 20, Polysorbate 40, Polysorbate 60 andPolysorbate 80.

The term “polysorbate aggregate” as used herein is a broad term and isto be given its ordinary and customary meaning to a person of ordinaryskill in the art and is not to be limited to a special or customizedmeaning. The term specifically may refer, without limitation, toaccumulations of polysorbate molecules. These polysorbate aggregates maybe, e.g., found in solutions comprising polysorbates stored at roomtemperature.

The term “reducing the formation of polysorbate aggregate formation” asused herein is a broad term and is to be given its ordinary andcustomary meaning to a person of ordinary skill in the art and is not tobe limited to a special or customized meaning. The term specifically mayrefer, without limitation, to the fact that the number of aggregatesformed by or comprising polysorbate molecules and/or a capability ofpolysorbate molecules to form or contribute to a generation ofaggregates comprising polysorbate molecules in a liquid drug productshall be reduced compared to a control product after applying the methodas described above. A typical control product in this context may be aliquid drug product which has not been treated by the method of thisdisclosure.

Experimental techniques to determine aggregation formation, typically,include spectrometric methods, such as optical spectroscopy and lightscattering techniques, or size exclusion chromatography methods.

The reduced formation of polysorbate aggregate formation due to applyingthe method of this disclosure as referred to herein may be determined bycomparing the number of polysorbate aggregates formed in a sample of aliquid drug product which has been treated by the method of thisdisclosure and the number of polysorbate aggregates formed in a sampleof a control liquid drug product, e.g., a liquid drug product which hasnot been treated by the method of this disclosure. A successfultreatment will be accompanied by reduction of the number of aggregatesin the treated sample versus the control sample. Typically, such acomparison of polysorbate aggregate determinations may be done atvarious time points in the future after treatment, e.g., in a timecourse measurement.

Thanks to the method of this disclosure, the formation ofdisadvantageous polysorbate aggregates in liquid drug products can besignificantly increased which results in, e.g., better storage andhandling capabilities for the product as well as betterbiocompatibility.

The method of reducing the formation of polysorbate aggregate formationin a liquid drug product may comprise using the degassing device and/orthe drug product filling device as described above and/or as describedfurther below.

The method may further comprise the following step:

-   -   Z. filling the degassed liquid drug product into at least one        container.

The proposed methods and device, in particular the drug product fillingdevice the method of filling at least one drug product into containersand the method of increasing the accuracy of the filling weight of aliquid drug product in a container, provide a large number of advantagesover known methods and devices of similar kind.

In particular, the proposed methods and device may reduce the amount ofgas dissolved in or comprised by the liquid drug product. The proposedmethods and device may thus reduce or suppress a presence, a formationor a nucleation of gas bubbles in the drug product, specifically in thedrug product filled in containers. Gas bubbles comprised by the drugproduct in the container may mistakenly be identified as particles,e.g., by an optical inspection of the containers after filling thecontainers with the liquid drug product. This may lead to an erroneousidentification of the filled container as being defective, e.g., by afully or partially automated inspection machine, and may thus lead to anerroneous identification of filled containers as rejects. The proposedmethods and device may reduce the erroneous identification of filledcontainers as rejects due to the presence of bubbles and may increasethe yield by at least partially separating off the at least one gas fromthe liquid drug product. Further, the proposed methods and device mayreduce a need, expenses and/or costs for steps or measures necessary toidentify containers filled with drug product, which were separated outerroneously. Thus, the proposed methods and device may increase theyield of the containers filled with liquid drug product by means ofremoving of reducing gas bubbles that could be mistaken for particlesduring a visual inspection.

Further, the proposed methods and device may be less time-consuming thanknown methods and devices since the proposed methods and device may takeplace continuously, such as in an in-line fashion, as part of thefilling of the liquid drug product into containers and not as a separatestep as is common for methods and devices of similar kind known in theart. Moreover, the proposed methods and device may render one or severalsteps unnecessary, such as, for example, a temporary storage of thecontainers filled with drug product, which may specifically take severalhours or even days, before an optical inspection may be carried out.Thus, the proposed methods and device may reduce costs, time and/oreffort involved in the process of filling the liquid drug product intocontainers. Thus, the efficiency of filling the liquid drug product intocontainers may be increased.

Furthermore, it may be possible that the proposed method and device maybe more effective in separating off the at least one gas from the liquiddrug product than methods and devices of similar kind known in the art.In particular, it may be possible that the proposed method and devicemay completely or partially avert a renewed import or discharge of theat least one gas into the liquid drug product after use of the proposeddevice or after performing the proposed method since the gas may beseparated off from the liquid drug product directly before the drugproduct is filled into the containers. In particular, a renewed contactof the liquid drug product with gases, e.g., with gaseous nitrogen, maybe avoided.

Moreover, it may be possible that at least partially separating off atleast one gas from the liquid drug product may have no effect on theconcentration of the drug product, specifically on the concentration ofone or several active components of the liquid drug product.Alternatively, at least partially separating off at least one gas fromthe liquid drug product may have a negligible effect on theconcentration of the drug product, specifically on the concentration ofone or several active components of the liquid drug product. Further, itmay be possible that the degassing device may comprise only materialswhich are approved for being used in producing drug products, inparticular approved by the Food and Drug Administration.

Further, it may be possible that the proposed method of filling at leastone liquid drug product into containers, the proposed method ofincreasing the accuracy of the filling weight of a liquid drug productin a container and/or the proposed drug product filling device mayincrease the accuracy of the filling weight of the liquid drug productin the container as compared to methods and devices of similar kindknown in the art. Evidence may, e.g., be found in the experimental datadisplayed in Table 3. The increased accuracy as compared to conventionalmethods and devices of similar kind may in particular be due to at leastpartially separating off at least one gas from the liquid drug productsince the presence of gas, e.g., in the form of bubbles may for examplereduce the portion of liquid drug product comprised in a given volume.

Furthermore, it may be possible that the proposed methods and device maycontribute to a stability of the liquid drug product, specifically tothe at least one active component of the liquid drug product, inparticular by at least partially separating off at least one gas fromthe liquid drug product. This may be due to the fact that the presenceof microbubbles may induce or support a formation of aggregates ofmolecules, in particular molecules acting as active components of a drugproduct such as proteins, protein fragments, antibodies and antibodyfragments, as suggested, e.g., by Giannos and colleagues (Giannos S A,Kraft E R, Zhao Z Y, Merkley K H, Cai J. “Formulation Stabilization andDisaggregation of Bevacizumab, Ranibizumab and Aflibercept in DiluteSolutions.” Pharm Res. 2018 Feb. 28; 35(4):78. doi:10.1007/s11095-018-2368-7). A further contribution to the stability ofthe liquid drug product, specifically to the at least one activecomponent of the liquid drug product, in particular to a protein, may bedue to the fact that degassing the liquid drug product may avoid or atleast reduce a formation of aggregates of polysorbate, which may bepresent in the liquid drug product.

Moreover, it may be possible that the proposed methods and device mayreduce a time span necessary for filling a number of containers, such asa batch or a lot, with a liquid drug product, specifically with adegassed liquid drug product, or a time span necessary for filling acertain volume of degassed drug product into containers. This may be dueto the fact that the proposed methods and devices may render redundantlengthy degassing steps, in particular degassing steps that cannot becarried out in an in-line fashion but that have to be carried out asseparate, non-continuous steps taking place in addition to the fillingprocess. Thus, the proposed methods and device may be lesstime-consuming than methods and devices of similar kind known in theart.

Summarizing and without excluding further possible embodiments, thefollowing embodiments may be envisaged:

Embodiment 1: A drug product filling device for filling at least onedrug product into containers, comprising:

-   a) at least one drug product preparation device, the drug product    preparation device being configured for preparing the liquid drug    product;-   b) at least one filling station for filling the liquid drug product    into the containers, the filling station being fluidically coupled    to the drug product preparation device; and-   c) at least one degassing device, the degassing device being    fluidically interposed in between the drug product preparation    device and the filling station and the degassing device comprising    at least one membrane for at least partially separating off at least    one gas from the liquid drug product.

Embodiment 2: The drug product filling device according to the precedingembodiment, wherein the membrane has a thickness of 25 μm to 200 μm,preferably 25 μm to 100 μm, more preferably 40 μm to 70 μm, mostpreferably of 55 μm.

Embodiment 3: The drug product filling device according to any one ofthe preceding embodiments, wherein the degassing device is configuredfor applying a pressure difference over the membrane, with the liquiddrug product being in contact with the membrane on a first side and withan opposing second side of the membrane being exposed to a lowerpressure than the first side.

Embodiment 4: The drug product filling device according to the precedingembodiment, wherein the pressure difference over the membrane is 0.1 barto 3.0 bar, preferably 0.6 bar to 1.0 bar, more preferably 0.8 bar.

Embodiment 5: The drug product filling device according to any one ofthe two preceding embodiments, wherein the degassing device comprises atleast one of a vacuum source or a vacuum port for applying a vacuum tothe second side.

Embodiment 6: The drug product filling device according to any one ofthe preceding embodiments, wherein the drug product, in the degassingdevice, has an absolute pressure of 0.1 bar to 3.0 bar, preferably 0.6to 1.0 bar, more preferably 0.8 bar.

Embodiment 7: The drug product filling device according to any one ofthe preceding embodiments, wherein the degassing device comprises atleast one hollow fiber membrane module comprising a plurality of hollowfibers, wherein the hollow fibers are at least partially formed by themembrane.

Embodiment 8: The drug product filling device according to the precedingembodiment, wherein the hollow fibers form fiber bundles.

Embodiment 9: The drug product filling device according to the precedingembodiment, wherein the fiber bundles, on both ends, are embedded in asealing.

Embodiment 10: The drug product filling device according to any one ofthe two preceding embodiments, wherein ends of the fiber bundles areconnected to connection ports.

Embodiment 11: The drug product filling device according to any one ofthe four preceding embodiments, wherein the hollow fiber membrane modulecomprises at least one housing, the housing having the hollow fibersdisposed therein.

Embodiment 12: The drug product filling device according to thepreceding embodiment, wherein the hollow fiber membrane module comprisesat least one fiber entry port connected to a first end of the hollowfibers, at least one fiber exit port connected to a second end of thehollow fibers, and at least one housing entry port and at least onehousing exit port, both the housing entry port and the housing exit portbeing connected to at least one inner space inside the housing betweenthe hollow fibers and a wall of the housing.

Embodiment 13: The drug product filling device according to thepreceding embodiment, wherein the hollow fiber membrane module isfluidically interposed in between the drug product preparation deviceand the filling station in a way selected from the group consisting of:

-   i) the fiber entry port is directly or indirectly fluidically    connected to the drug product preparation device, and the fiber exit    port is directly or indirectly fluidically connected to the filling    station; or-   ii) the housing entry port is directly or indirectly fluidically    connected to the drug product preparation device, and the housing    exit port is directly or indirectly fluidically connected to the    filling station.

Embodiment 14: The drug product filling device according to thepreceding embodiment, wherein option i) is selected, wherein one or bothof the housing entry port and the housing exit port are connected to asuction device, specifically for applying a vacuum to the inner space.

Embodiment 15: The drug product filling device according to any one ofthe two preceding embodiments, wherein option ii) is chosen, wherein oneor both of the fiber entry port and the fiber exit port are connected toa suction device, specifically for applying a vacuum to the inside ofthe hollow fibers.

Embodiment 16: The drug product filling device according to any one ofthe preceding embodiments, wherein the membrane comprises at least onematerial selected from the group consisting of: polydimethylsiloxane(PDMS); cellulose acetate (CA), polysulfone (PS), polyether sulfone(PES), polyacrilonitrile (PAN), polyvinylidiene fluoride (PVDF),poylpropylene (PP), polyethylene (PE), polyvinyl chloride (PVC),polytetrafluoroethylene (PTFE) and silicone, preferably the membranecomprises silicone.

Embodiment 17: The drug product filling device according to any one ofthe preceding embodiments, wherein the degassing device has at least oneentry port connected to the drug product preparation device and at leastone exit port connected to the filling station.

Embodiment 18: The drug product filling device according to any one ofthe preceding embodiments, wherein the degassing device is interposed inbetween the drug product preparation device and the filling station inan in-line fashion.

Embodiment 19: The drug product filling device according to any one ofthe preceding embodiments, further comprising at least one in-linefiltering device fluidically interposed in between the drug productpreparation device and the filling station.

Embodiment 20: The drug product filling device according to thepreceding embodiment, wherein the in-line filtering device comprises asterile filter and optionally a prefilter for reducing the bioburden.

Embodiment 21: The drug product filling device according to any one ofthe preceding embodiments, wherein the degassing device is at leastpartially sterilizable.

Embodiment 22: The drug product filling device according to any one ofthe preceding embodiments, further comprising at least one transfersystem configured for transferring the drug product from the drugproduct preparation device to the filling station wherein the transfersystem has at least one of: a gas supply; a pump.

Embodiment 23: The drug product filling device according to thepreceding embodiment, wherein a pressure for transferring the drugproduct from the drug product preparation device to the filling stationis 0.8 bar to 1.0 bar.

Embodiment 24: The drug product filling device according to any one ofthe preceding embodiments, wherein the filling station further comprisesat least one inspection device for optically inspecting the containersafter filling with the liquid drug product.

Embodiment 25: The drug product filling device according to thepreceding embodiment, wherein the filling station further comprises atleast one selection device having at least one controller forautomatically recognizing defective containers and for automaticallyremoving defective containers.

Embodiment 26: The drug product filling device according to any one ofthe two preceding embodiments, wherein the inspection device comprisesat least one camera and at least one image recognition device.

Embodiment 27: The drug product filling device according to any one ofthe preceding embodiments, wherein the filling station further comprisesat least one closing station for closing the containers by at least oneof: stopper; a cap, particularly a Plascap®; a sealing.

Embodiment 28: The drug product filling device according to thepreceding embodiment, wherein the closing station further comprises atleast one crimping station for fixation of at least one of: the stopper,the cap, particularly the Plascap®, the seal; e.g., by crimping.

Embodiment 29: The drug product filling device according to any one ofthe preceding embodiments, wherein the drug product preparation deviceis configured for preparing the liquid drug product from at least twocomponents.

Embodiment 30: The drug product filling device according to any one ofthe preceding embodiments, wherein the drug product preparation devicecomprises at least one mixing vessel for mixing at least two componentsof the drug product.

Embodiment 31: The drug product filling device according to thepreceding embodiment, wherein the mixing vessel comprises at least onestirring device for stirring the drug product.

Embodiment 32: The drug product filling device according to any one ofthe preceding embodiments, wherein the drug product preparation devicecomprises at least one of: a storage vessel; a transport vessel; whereinthe storage vessel and/or the transport vessel is fluidically connectedto the filling station.

Embodiment 33: The drug product filling device according to thepreceding embodiment, wherein the storage vessel comprises at least onetempering device for one or both of cooling or heating the drug product.

Embodiment 34: The drug product filling device according to any one ofthe two preceding embodiments, wherein the storage vessel comprises atleast one gas supply for supplying at least one shielding gas into thestorage vessel and for storing the drug product under the shielding gas.

Embodiment 35: The drug product filling device according to thepreceding embodiment, wherein the gas supply comprises at least onenitrogen supply.

Embodiment 36: The drug product filling device according to any one ofthe preceding claims, wherein the drug product has a viscosity from 0.2mPa s to 30 mPa s, preferably from 1 mPa s to 20 mPa s, more preferably1 mPa s to 5 mPa s, most preferably 1 mPa s to 1.5 mPa s.

Embodiment 37: The drug product filling device according to any of thepreceding embodiments, wherein the at least one membrane has a contactarea for being in contact with the drug product, wherein a size of thecontact area is 10 cm² to 5 m², preferably 0.5 m² to 1.5 m², morepreferably the size of the contact area is 1 m².

Embodiment 38: The drug product filling device according to any of thepreceding claims, wherein the drug product filling device is configuredfor conducting the drug product through the degassing device at a rateof 5 L/h to 150 L/h, preferably of 60 L/h to 100 L/h, more preferably ata rate of 70 L/h to 90 L/h.

Embodiment 39: The drug product filling device according to any of thepreceding embodiment, wherein the drug product has a temperature of 0°C. to 25° C.

Embodiment 40: The drug product filling device according to any of thepreceding embodiments, wherein the drug product filling device furthercomprises a coupling bow having at least one first coupling access andat least one second coupling access, wherein the degassing device isdirectly or indirectly fluidically connectable to the drug productpreparation device via the first coupling access, wherein the degassingdevice is directly or indirectly fluidically connectable to the fillingstation via the second coupling access.

Embodiment 41: The drug product filling device according to thepreceding embodiment, wherein the coupling bow further comprises atleast one holder for mounting the degassing device.

Embodiment 42: A method of filling at least one drug product intocontainers, comprising:

-   A) providing at least one drug product filling device configured for    filling at least one liquid drug product into containers, wherein    providing the drug product filling device comprises:    -   providing at least one drug product preparation device, the drug        product preparation device being configured for preparing the        liquid drug product;    -   providing at least one filling station for filling the liquid        drug product into the containers, the filling station being        fluidically coupled to the drug product preparation device;    -   providing at least one degassing device being fluidically        interposed in between the drug product preparation device and        the filling station and the degassing device comprising at least        one membrane for separating off at least one gas from the liquid        drug product;-   B) conducting the drug product from the drug product preparation    device to the filling station, wherein the drug product is at least    partially degassed upon passing through the degassing device; and-   C) filling the at least partially degassed drug product into the    containers by means of the filling station.

Embodiment 43: The method according to the preceding embodiment, step B)further comprising:

-   -   applying a pressure difference over the membrane using the        degassing device, with the liquid drug product being in contact        with the membrane on a first side and with an opposing second        side of the membrane being exposed to a lower pressure than the        first side.

Embodiment 44: The method according to the preceding embodiment, whereinthe degassing device is configured for applying the pressure differenceover the membrane by comprising at least one of a vacuum source or avacuum port for applying a vacuum to the second side.

Embodiment 45: The method according to any one of the preceding methodembodiments, wherein the degassing device comprises at least one hollowfiber membrane module comprising a plurality of hollow fibers, whereinthe hollow fibers are at least partially formed by the membrane.

Embodiment 46: The method according to the preceding method embodiment,wherein the hollow fibers form fiber bundles.

Embodiment 47: The method according to any one of the preceding methodembodiment, step B) further comprising:

-   -   conducting the drug product from the drug product preparation        device to the filling station by at least sectionally using a        stream of transport gas.

Embodiment 48: The method according to the preceding embodiment, whereinthe transport gas is nitrogen.

Embodiment 49: The method according to any one of the preceding methodembodiments, wherein a drug product filling device according to any ofthe preceding claims concerning a drug product filling device is used.

Embodiment 50: The method according to any one of the preceding methodembodiments, wherein the accuracy of the filling weight of the liquiddrug product in the container is increased.

Embodiment 51: The method according to any one of the preceding methodembodiments, wherein the stability of at least one oxygen-sensitiveactive pharmaceutical ingredient in the liquid drug product isincreased.

Embodiment 52: The method according to any one of the preceding methodclaims, wherein polysorbate aggregate formation in the liquid drugproduct is reduced.

Embodiment 53: A method of increasing the accuracy of the filling weightof a liquid drug product in a container, the method comprising:

-   I. preparing the at least one liquid drug product;-   II. degassing the liquid drug product by at least partially    separating off at least one gas from the liquid drug product by    using a degassing device, the degassing device comprising at least    one membrane;-   III. filling the degassed liquid drug product into the container.

Embodiment 54: The method according to the preceding embodiment, whereinthe method comprises using the degassing device as described in any oneof the preceding embodiments referring to a drug product filling device.

Embodiment 55: The method according to any one of the two precedingembodiments, wherein the method comprises using the drug product fillingdevice as described in any one of the preceding embodiments referring toa drug product filling device.

Embodiment 56: A method of increasing the stability of at least oneoxygen-sensitive active pharmaceutical ingredient, in particular aprotein, in a liquid drug product, specifically a liquid drug product ina container, the method comprising:

-   α. preparing the at least one liquid drug product, the liquid drug    product comprising at least one oxygen-sensitive active    pharmaceutical ingredient, in particular a protein; and-   β. degassing the liquid drug product by at least partially    separating off at least one gas from the liquid drug product by    using a degassing device, the degassing device comprising at least    one membrane.

Embodiment 57: The method according to the preceding embodiment, whereinthe method comprises using the degassing device as described in any oneof the preceding embodiments referring to a drug product filling device.

Embodiment 58: The method according to any one of the two precedingembodiments, wherein the method comprises using the drug product fillingdevice according to any one of the preceding embodiments referring to adrug product filling device.

Embodiment 59: The method according to any one of the three precedingembodiments, further comprising:

-   -   γ. filling the degassed liquid drug product into at least one        container.

Embodiment 60: A method of reducing polysorbate aggregate formation in aliquid drug product, specifically a liquid drug product in a container,the method comprising:

-   -   X. preparing the at least one liquid drug product, the liquid        drug product comprising at least one oxygen-sensitive active        pharmaceutical ingredient, in particular a protein, and at least        one polysorbate; and    -   Y. degassing the liquid drug product by at least partially        separating off at least one gas from the liquid drug product by        using a degassing device, the degassing device comprising at        least one membrane.

Embodiment 61: The method according to the preceding embodiment, whereinthe method comprises using the degassing device as described in any oneof the preceding embodiments referring to a drug product filling device.

Embodiment 62: The method according to any one of the two precedingembodiments, wherein the method comprises using the drug product fillingdevice according to any one of the preceding embodiments referring to adrug product filling device.

Embodiment 63: The method according to any one of the three precedingembodiments, further comprising:

-   -   Z. filling the degassed liquid drug product into at least one        container.

BRIEF DESCRIPTION OF THE DRAWINGS

The above-mentioned aspects of exemplary embodiments will become moreapparent and will be better understood by reference to the followingdescription of the embodiments taken in conjunction with theaccompanying drawings, wherein:

FIGS. 1A and 1B show a sectional view of a drug product filling devicecomprising a coupling bow (1A) and a degassing device inserted into aholder of the coupling bow (1B);

FIGS. 2A and 2B show an exploded view of the degassing device (2A) and adetailed view of a hollow fiber of a fiber bundle comprised by thedegassing device;

FIG. 3 shows a further view of the degassing device;

FIG. 4 shows an experimental setup for testing a function of separatingoff oxygen from the liquid drug product by the degassing device;

FIGS. 5A, 5B, 5C and 5D show measuring diagrams illustrating an oxygencontent in the drug product as a function of time for different flowrates of the drug product (5A, 5B and 5C) and illustrating an oxygenseparation efficiency as a function of the flow rate of the drug product(5D);

FIG. 6 shows a method of filling a drug product into containers;

FIG. 7 shows a method of increasing the accuracy of the filling weightof a liquid drug product in a container;

FIG. 8 shows a method of increasing the stability of an oxygen-sensitiveactive pharmaceutical ingredient in a liquid drug product; and

FIG. 9 shows a method of reducing the formation of polysorbate aggregateformation in a liquid drug product.

DESCRIPTION

The embodiments described below are not intended to be exhaustive or tolimit the invention to the precise forms disclosed in the followingdetailed description. Rather, the embodiments are chosen and describedso that others skilled in the art may appreciate and understand theprinciples and practices of this disclosure.

FIG. 1A shows a sectional view of a drug product filling device 110configured for filling at least one liquid drug product into containers.The drug product filling device 110 comprises at least one drug productpreparation device (drug product preparer) 112, the drug productpreparation device 112 being configured for preparing the liquid drugproduct. The drug product filling device 110 further comprises at leastone filling station 114 for filling the liquid drug product into thecontainers, the filling station 114 being fluidically coupled to thedrug product preparation device 112 as also depicted in FIG. 1A. Asfurther illustrated in FIG. 1A, the drug product filling 114 devicefurthermore comprises at least one degassing device (degasser) 116, thedegassing device 116 being fluidically interposed in between the drugproduct preparation device 112 and the filling station 114. Thedegassing device 116 comprises at least one membrane 118 for at leastpartially separating off at least one gas from the liquid drug product.As also shown in FIG. 1A, the drug product filling 110 device mayfurther comprise a coupling bow 120 having at least one first couplingaccess 122 and at least one second coupling access 124, wherein thedegassing device 116 may be fluidically connectable to the drug productpreparation device 112 via the first coupling access 122, wherein thedegassing device 116 may be fluidically connectable to the fillingstation 114 via the second coupling access 124.

FIG. 1B shows a detailed view of the coupling bow 120. As can be seen,the degassing device may be fluidically connected to the first couplingaccess 122 by a first flexible tube 126 and the degassing device may befluidically connected to the second coupling access 124 by a secondflexible tube 128. Thus, the degassing device 116 may be indirectlyfluidically coupled to the drug product preparation device 112 and thefilling station 114, wherein the indirect fluidic connection with thedrug product preparation device 112 may be established at least by thefirst coupling access 122 and the first flexible tube 126 and theindirect fluidic connection with the filling station 114 may beestablished at least by the second coupling access 124 and the secondflexible tube 128. The coupling bow 120 may further comprise at leastone holder 130 for mounting the degassing device 116. Additionally oralternatively, the drug product filling device 110, in particular thedrug product preparation device 112 and/or the filling station 114, maycomprise the holder 130 for mounting the degassing device 116 (not shownin the Figures). In particular the holder 130 may be configured toremovably receive the degassing device 116, as, e.g., shown in FIG. 1B.In particular, the degassing device may be or may comprise a PermSelect®Silicone Membrane Module as available from MedArray Inc., Ann Arbor,Mich. 48108, U.S.A., such as the hollow fiber membrane modulePDMSXA-2500 and/or the hollow fiber membrane module PSMSXA-1.0.

FIG. 2A shows an exploded view of the degassing device 116. Thedegassing device 116 comprises at least one membrane 118 for separatingoff gases from the liquid drug product. Specifically, the membrane maycomprise at least one material selected from the group consisting of:polydimethylsiloxane (PDMS); cellulose acetate (CA), polysulfone (PS),polyether sulfone (PES), polyacrilonitrile (PAN), polyvinylidienefluoride (PVDF), poylpropylene (PP), polyethylene (PE), polyvinylchloride (PVC), polytetrafluoroethylene (PTFE) and silicone, preferablythe membrane comprises silicone. In particular, the membrane may have athickness of 25 μm to 100 μm, preferably 40 μm to 70 μm, more preferablyof 55 μm. As depicted in FIG. 2A, the degassing device 116 mayspecifically comprise at least one hollow fiber membrane module 132comprising a plurality of hollow fibers 134, wherein the hollow fibers134 are at least partially formed by the membrane 118. Specifically, thehollow fibers 134 may have an inner diameter and an outer diameter,wherein the inner diameter may have a value of 50 μm to 800 μm,preferably of 150 μm to 250 μm, more preferably a value of 190 μm, andwherein the outer diameter may have a value of 75 μm to 900 μm,preferably of 150 μm to 450 μm, more preferably a value of 300 μm. Inparticular, the thickness of the membrane may be 55 μm, the innerdiameter of the hollow fiber 134 may be 190 μm and the outer diameter ofthe hollow fiber 134 may be 300 μm. The hollow fiber 134 may at leastpartially define or comprises an interior space or lumen 135. Inparticular, the interior space or lumen 135 of the hollow fiber 134 mayalso be referred to as an inside of the hollow fiber 134. Further, theplurality of hollow fibers 134 of the hollow fiber membrane module 132may comprise a number of 30 hollow fibers 134 to 30000 hollow fibers134. The number of the hollow fibers 134 of the hollow fiber membranemodule 132 may in particular depend on a size of the hollow fibermembrane module 132, in particular on an overall membrane 118 area,i.e., on the sum of membrane 118 areas of all hollow fibers 134 in thehollow fiber membrane module 132, and/or on a cross sectional area ofthe hollow fiber membrane module 132, wherein the cross sectional areamay be perpendicular to a main direction of extension, in particular toa length, of the hollow fiber membrane module 132.

As an example, the fiber count per unit membrane 118 area may be in therange of 1.0 to 4.0 fibers/cm², e.g., 1 to 3 fibers/cm², preferably 1 to1.5 fibers/cm², more preferably 1.26 to 1.42 fibers/cm². Additionally oralternatively, the number of hollow fibers 1324, specifically a fibercount, per cross sectional area unit of the hollow fiber membrane module132 may be 20 cm⁻² to 800 cm⁻², such as 40 cm⁻² to 500 cm⁻², e.g., 42cm⁻² to 483 cm⁻².

In particular, the number of hollow fibers 134 per cross sectional areaunit of the hollow fiber membrane module 132 may be from 20 cm⁻² to 800cm⁻², preferably form 40 cm⁻² to 570 cm⁻².

Furthermore, the hollow fibers 134 may have a length of 10 cm to 16 cm,preferably of 10 cm to 15 cm, more preferably of 10 cm to 12 cm. Furtherthe hollow fiber membrane module 132 may have a length of 10 cm to 16cm, preferably of 10 cm to 16 cm, more preferably of 11 cm to 15 cm,most preferably of 14 cm. FIG. 2A further illustrates that the hollowfibers 134 may, specifically, form fiber bundles 136. In particular, thefiber bundles 136, on both ends, may be embedded in a sealing 138.Further, the ends of the fiber bundles 136 may be connected toconnection ports 140 as illustrated in FIG. 2A. The hollow fibermembrane module 132 may further comprise at least one housing 142, thehousing 142 having the hollow fibers 134 disposed therein. Furthermore,the hollow fiber membrane module 132 may comprise at least one fiberentry port connected to a first end of the hollow fibers, at least onefiber exit port connected to a second end of the hollow fibers, and atleast one housing entry port and at least one housing exit port, boththe housing entry port and the housing exit port being connected to atleast one inner space inside the housing between the hollow fibers and awall of the housing.

A fluid, in particular a gas or a liquid, may be introduced into thefibers via the fiber entry port. In particular, in the case of the fluidbeing a gas, the fiber entry port may also be used as a fiber exit port.Thus, as described further below, a vacuum may be applied to the insideof the hollow fiber by connecting one or both of the fiber entry portand the fiber exit port to a suction device.

A fluid, in particular a gas or a liquid, may be introduced into theinner space of the housing via the fiber entry port. In particular, inthe case of the fluid being a gas, the housing entry port may also beused as a housing exit port. Thus, as described further below, a vacuummay be applied to the inner space by connecting one or both of thehousing entry port and the housing exit port to a suction device.

A fluid, in particular a gas or a liquid, contained in inner space ofthe housing may be exported from the inner space of the housing via thehousing exit port.

FIG. 2B illustrates a detailed view of the hollow fiber 134 of the fiberbundle 136 comprised by the degassing device 116. The degassing device116 may particularly be configured for applying a pressure differenceover the membrane 118, with the liquid drug product being in contactwith the membrane on a first side 144 and with an opposing second side146 of the membrane 118 being exposed to a lower pressure than the firstside 144. Thus, the pressure difference may be the difference betweenthe magnitude of the pressure on the first side 144 and the magnitude ofthe pressure on the second side 146. Specifically, the pressuredifference over the membrane 118 may be 0.1 bar to 3.0 bar, preferably0.6 bar to 1.0 bar, more preferably 0.8 bar. Further, the degassingdevice 116 may comprise at least one of a vacuum source (not shown inthe Figures) or a vacuum port 148 for applying a vacuum to the secondside 146. Specifically, the vacuum source may comprise at last one pump.In particular, an absolute value of the vacuum applied to the secondside 146 may be 0.010 bar to 0.900 bar, preferably, 0.010 to 0.020 bar,more preferably 0.015 bar. In FIG. 2B, solid arrows illustrate adirection of motion of the liquid drug product, which may enter thedegassing device 116 via a fiber entry port 150 to be led through thehollow fibers 134 for being at least partially degassed. As alsoindicated by the solid arrow, the liquid drug product may then leave thehollow fiber membrane module 132 via a fiber exit port 152 being atleast partially degassed. Thus, the connection port 140 connected to oneend of the fiber bundle 136 may be implemented as the fiber entry port150 and the connection port 140 at the other end of the fiber bundle 136may be implemented as a fiber exit port 152. Further, the fiber entryport 150 may be connected to the drug product preparation device and thefiber exit port may be connected to the filling station (not shown inFIG. 2B). Dashed arrows illustrate a direction of motion of the at leastone gas which is separated off from the liquid drug product by means ofthe degassing device 116. Specifically, the drug product, in thedegassing device 116, may have an absolute pressure of 0.1 bar to 3.0bar, preferably 0.6 bar to 1.0 bar, more preferably 0.8 bar.Furthermore, the hollow fiber membrane module 132 may comprise at leastone housing entry port and at least one housing exit port, both thehousing entry port and the housing exit port being connected to at leastone inner space 154 inside the housing 142 between the hollow fibers 134and a wall 156 of the housing 142.

FIG. 3 illustrates a further view of the degassing device 116. Thedegassing device 116 is fluidically interposed in between the drugproduct preparation device 112 and the filling station 114.Specifically, the hollow fiber membrane module 132 may be fluidicallyinterposed in between the drug product preparation device 112 and thefilling station 114 in a way selected from the group consisting of:

-   i) the fiber entry port 150 may be directly or indirectly    fluidically connected to the drug product preparation device 112,    and the fiber exit port 152 may be directly or indirectly    fluidically connected to the filling station 114; or-   ii) the housing entry port may be directly or indirectly fluidically    connected to the drug product preparation device, and the housing    exit port may be directly or indirectly fluidically connected to the    filling station (not shown in the Figures).

FIG. 3 shows a sectional view of option i) with particular attention onthe degassing device 116. As illustrated in FIGS. 3 and 2B, theconnection port 140 connected to one end of the fiber bundle 136 may beimplemented as the fiber entry port 150 and the connection port 140 atthe other end of the fiber bundle 136 may be implemented as a fiber exitport 152. Again, dashed arrows illustrate a direction of motion of theat least one gas which is separated off from the liquid drug product bymeans of the degassing device 116. In the case as depicted in FIG. 3,the liquid drug product may flow through the lumen 135 of the hollowfibers 134 and the gas separated off from the liquid drug product may bediscarded via the vacuum ports 148. If option ii) is chosen (not shownin the Figures), the liquid drug product may flow through the innerspace 154 of the housing 142. Thus, in the case of option ii), thevacuum ports 148 as shown in FIG. 3 may be used as housing entry portand housing exit port, respectively, and the connection ports 140 may beused as vacuum ports 148. A further opening 157 may remain closed inboth option i) and option ii).

FIG. 4 shows an experimental setup 158 for testing a function ofseparating off oxygen as an exemplary gas from the liquid drug productby the degassing device 116. The experimental setup 158 comprises thedegassing device 116, which is fluidically interposed in between areservoir 160 of the liquid drug product and a collecting receptacle162. Nitrogen gas is guided through at least one nitrogen supply tube163 to the reservoir to generate a pressure required to deliver the drugproduct to the degassing device 116 via at least one delivery tube 164.The pressure of the nitrogen in the nitrogen supply tube 163 isadjustable by a pressure reducer 165. A flow meter 166 determines avolume flow per time unit of the drug product through the delivery tube164. A pressure transmitter 168 monitors the pressure in the deliverytube 164. The degassing device 116 is further connected to thecollection receptacle 162 via at least one receiving tube 170, whichguides the at least partially degassed drug product to the receptacle162. An oxygen sensor 172 connected to an oxygen meter 173 determines anoxygen content of the at least partially degassed liquid drug product inthe receiving tube 170. A vacuum is applied by means of at least onevacuum pump 174 in conjunction with at least one peristaltic pump 176such that the second side 146 of the membrane 118 is exposed to a lowerpressure than the first side 144 of the membrane 118. The experimentalsetup 158 further comprises a vacuum controller 178, a vacuum reservoir180 and a power supply 182. The experimental setup 158 may comprisefurther elements that may not be shown in FIG. 4 and/or that may not bementioned or described.

Further experimental setups 158, which are not shown in the Figures, areused to investigate and/or evaluate further aspects of the drug productfilling device. In particular, an effect of the degassing device on aconcentration of at least one active component of the liquid drugproduct may be investigated, e.g., by using a cold trap that may trapcollected water.

FIGS. 5A, 5B and 5C show measuring diagrams plotting the oxygen contentin percent 184 of the liquid drug product on the left x-axis as afunction of time in seconds 186. The start value of the oxygen content,therein, is arbitrarily set to be 100%. The point in time at which thevacuum is applied is demarcated by a straight vertical line. The x-axison the right hand side indicates the oxygen content in mg/L 188. FIGS.5A, 5B and 5C all refer to an experimental set-up with a vacuum of 100mbar applied to the second side of the membrane 118 and differing flowrates of 10 L/h (5A), 20 L/h (5B) and 40 L/h (5C). The measuringdiagrams in FIGS. 5A, 5B and 5C show a decrease in the oxygen contentcomprised by the liquid drug product as a function of the time for allflow rates. FIG. 5D illustrates an oxygen separation efficiency 190 as afunction of the volume flow in L/h of the drug product showing oxygenseparation efficiencies of approximately 80% to 90% depending on thevolume flow.

In a second aspect of this disclosure a method of filling at least onedrug product into containers is disclosed. The method comprises thesteps disclosed in the following. The steps may specifically beperformed in the given order. Still, a different order is possible. Themethod may comprise additional steps which are not mentioned. It isfurther possible to perform one or more of the method steps repeatedly.Further, two or more of the method steps may be performed in a timelyoverlapping fashion or simultaneously.

As illustrated in FIG. 6, the method comprises in a first step A)(method step 194) providing at least one drug product filling device 110configured for filling at least one drug product into containers,wherein providing the drug product filling device comprises at least thesubsteps of providing at least one drug product preparation device 112,the drug product preparation device 112 being configured for preparing aliquid drug product (substep 196), providing at least one fillingstation 114 for filling the liquid drug product into the containers, thefilling station being fluidically coupled to the drug productpreparation device 112 (substep 198) and providing at least onedegassing device 116 being fluidically interposed in between the drugproduct preparation device 112 and the filling station 114 and thedegassing device 116 comprising at least one membrane 118 for separatingoff at least one gas from the liquid drug product (substep 200). Themethod further comprises in second step B (method step 202) conductingthe drug product from the drug product preparation device 112 to thefilling station 114, wherein the drug product is at least partiallydegassed upon passing through the degassing device 116. The methodfurther comprises in a third step C) (method step 204) filling the atleast partially degassed drug product into the containers by means ofthe filling station 114.

The method may comprise further steps, which are not shown in theFigures. In particular, step B) (method step 202) of the method mayfurther comprise applying a pressure difference over the membrane 118using the degassing device, with the liquid drug product being incontact with the membrane on a first side 144 and with an opposingsecond side 146 of the membrane 118 being exposed to a lower pressurethan the first side 144. In particular, the degassing device 116provided in step A) may be configured for applying the pressuredifference over the membrane 118 by comprising at least one of a vacuumsource or a vacuum port 148 for applying a vacuum to the second side146. The degassing device 116 may further comprise at least one hollowfiber membrane module 132 comprising a plurality of hollow fibers 134,wherein the hollow fibers 134 are at least partially formed by themembrane 118. The hollow fibers 134 may form fiber bundles 136. Further,step B) may specifically comprise conducting the drug product from thedrug product preparation device 112 to the filling station 114 by atleast sectionally using a stream of transport gas and/or a pump. Inparticular, the transport gas may be nitrogen. Further, the drug productfilling device 110 as provided in step A) (method step 194) mayspecifically be a drug product filling device 110 as described above oras described further below. Still, other embodiments are feasible.

In a third aspect of this disclosure, a method of increasing theaccuracy of the filling weight of a liquid drug product in a containeris disclosed. The method comprises the steps disclosed in the following.The steps may specifically be performed in the given order. Still, adifferent order is possible. The method may comprise additional stepswhich are not mentioned. It is further possible to perform one or moreof the method steps repeatedly. Further, two or more of the method stepsmay be performed in a timely overlapping fashion or simultaneously.

As illustrated in FIG. 7, the method comprises in a first step I.(method step 205) preparing the at least one liquid drug product. Themethod further comprises in a second step II. (method step 206)degassing the liquid drug product by at least partially separating offat least one gas from the liquid drug product by using a degassingdevice 116, the degassing device 116 comprising at least one membrane118. The method further comprises in a third step (method step 207)filling the degassed liquid drug product into the container.

In a fourth aspect of this disclosure, a method of increasing thestability of an oxygen-sensitive active pharmaceutical ingredient, suchas a protein, in a liquid drug product, specifically a liquid drugproduct in a container is disclosed. The method comprises the stepsdisclosed in the following. The steps may specifically be performed inthe given order. Still, a different order is possible. The method maycomprise additional steps which are not mentioned. It is furtherpossible to perform one or more of the method steps repeatedly. Further,two or more of the method steps may be performed in a timely overlappingfashion or simultaneously.

As illustrated in FIG. 8, the method comprises in a first step a.(method step 208) preparing the at least one liquid drug product, theliquid drug product comprising at least one oxygen-sensitive activepharmaceutical ingredient, such as a protein. The method furthercomprises in a second step fr (method step 210) degassing the liquiddrug product by at least partially separating off at least one gas fromthe liquid drug product by using a degassing device, the degassingdevice comprising at least one membrane. The method may further comprisein a third step (method step 212) filling the degassed liquid drugproduct into at least one container. The method may specificallycomprise using the degassing device as described above or as describedfurther below. Further, the method may particularly comprise using thedrug product filling device as described above or as described furtherbelow.

In a fifth aspect of this disclosure, a method of reducing the formationof polysorbate aggregate formation in a liquid drug product,specifically a liquid drug product in a container, is described. Themethod comprises the steps disclosed in the following. The steps mayspecifically be performed in the given order. Still, a different orderis possible. The method may comprise additional steps which are notmentioned. It is further possible to perform one or more of the methodsteps repeatedly. Further, two or more of the method steps may beperformed in a timely overlapping fashion or simultaneously.

As illustrated in FIG. 9, the method comprises in a first step (methodstep 214) preparing the at least one liquid drug product, the liquiddrug product comprising at least one oxygen-sensitive activepharmaceutical ingredient, such as a protein, and at least onepolysorbate. The method further comprises in a second step (method step216) degassing the liquid drug product by at least partially separatingoff at least one gas from the liquid drug product by using a degassingdevice, the degassing device comprising at least one membrane. Themethod may further comprise in a third step (method step 218) fillingthe degassed liquid drug product into at least one container. The methodmay specifically comprise using the degassing device as described aboveor as described further below. Further, the method may particularlycomprise using the drug product filling device as described above or asdescribed further below.

While exemplary embodiments have been disclosed hereinabove, the presentinvention is not limited to the disclosed embodiments. Instead, thisapplication is intended to cover any variations, uses, or adaptations ofthis disclosure using its general principles. Further, this applicationis intended to cover such departures from the present disclosure as comewithin known or customary practice in the art to which this inventionpertains and which fall within the limits of the appended claims.

LIST OF REFERENCE SIGNS

-   110 drug product filling device-   112 drug product preparation device-   114 filling station-   116 degassing device-   118 membrane-   120 coupling bow-   122 first coupling access-   124 second coupling access-   126 first flexible tube-   128 second flexible tube-   130 holder-   132 hollow fiber membrane module-   134 hollow fiber-   135 lumen-   136 fiber bundle-   138 sealing-   140 connection port-   142 housing-   144 first side of the membrane-   146 second side of the membrane-   148 vacuum port-   150 fiber entry port-   152 fiber exit port-   154 inner space-   156 wall-   157 further opening-   158 experimental setup-   160 reservoir-   162 collection receptacle-   163 nitrogen supply tube-   164 delivery tube-   165 pressure reducer-   166 flow meter-   168 pressure transmitter-   170 receiving tube-   172 oxygen sensor-   173 oxygen meter-   174 vacuum pump-   176 peristaltic pump-   178 vacuum controller-   180 vacuum reservoir-   182 power supply-   184 oxygen content in percent-   186 time in seconds-   188 oxygen content in mg/L-   190 oxygen separation efficiency-   192 volume flow in L/h-   194 providing at least one drug product filling device configured    for filling at least one liquid drug product into containers-   196 providing at least one drug product preparation device being    configured for preparing the liquid drug product-   198 providing at least one filling station for filling the liquid    drug product into containers, the filling station being fluidically    coupled to the drug product preparation device-   200 providing at least one degassing device being fluidically    interposed in between the drug product preparation device and the    filling station and the degassing device comprising at least one    membrane for separating off at least one gas from the liquid drug    product-   202 conducting the drug product from the drug product preparation    device to the filling station, wherein the drug product is at least    partially degassed upon passing through the degassing device-   204 filling the at least partially degassed drug product into the    containers by means of the filling station-   205 preparing the at least one liquid drug product-   206 degassing the liquid drug product by at least partially    separating off at least one gas from the liquid drug product by    using a degassing device, the degassing device comprising at least    one membrane-   207 filling the degassed liquid drug product into the container-   208 preparing the at least one liquid drug product, the liquid drug    product comprising at least one oxygen-sensitive active    pharmaceutical ingredient-   210 degassing the liquid drug product by at least partially    separating off at least one gas from the liquid drug product by    using a degassing device, the degassing device comprising at least    one membrane.-   212 filling the degassed liquid drug product into at least one    container-   214 preparing the at least one liquid drug product, the liquid drug    product comprising at least one oxygen-sensitive active    pharmaceutical ingredient and at least one polysorbate-   216 degassing the liquid drug product by at least partially    separating off at least one gas from the liquid drug product by    using a degassing device, the degassing device comprising at least    one membrane-   218 filling the degassed liquid drug product into at least one    container

What is claimed is:
 1. A drug product filling device for filling a liquid drug product into containers, comprising: a) a drug product preparer configured for preparing the liquid drug product; b) a filling station configured for filling the liquid drug product into the containers, the filling station being fluidly coupled to the drug product preparer; and c) a degasser fluidly interposed between the drug product preparer and the filling station, the degasser comprising a membrane configured for at least partially separating off at least one gas from the liquid drug product.
 2. The drug product filling device according to the claim 1, wherein the degasser is configured for applying a pressure difference over the membrane, with the liquid drug product being in contact with the membrane on a first side and with an opposing second side of the membrane being exposed to a lower pressure than the first side.
 3. The drug product filling device according to claim 2, wherein the degasser comprises at least one of a vacuum source or a vacuum port configured for applying a vacuum to the second side.
 4. The drug product filling device according to claim 1, wherein the degasser comprises a hollow fiber membrane module comprising a plurality of hollow fibers, wherein the hollow fibers are at least partially formed by the membrane.
 5. The drug product filling device according to claim 4, wherein the hollow fibers form fiber bundles.
 6. The drug product filling device according to claim 5, wherein the fiber bundles, on both ends, are embedded in a sealing.
 7. The drug product filling device according to claim 5, wherein ends of the fiber bundles are connected to connection ports.
 8. The drug product filling device according to claim 4, wherein the hollow fiber membrane module comprises a housing having the hollow fibers disposed therein.
 9. The drug product filling device according to claim 8, wherein the hollow fiber membrane module comprises a fiber entry port connected to a first end of the hollow fibers, a fiber exit port connected to a second end of the hollow fibers, and a housing entry port and a housing exit port, both the housing entry port and the housing exit port being connected to an inner space inside the housing between the hollow fibers and a wall of the housing.
 10. The drug product filling device according to claim 9, wherein the hollow fiber membrane module is fluidly interposed between the drug product preparer and the filling station in a manner selected from the group consisting of the following options: i) the fiber entry port is fluidly connected to the drug product preparer, and the fiber exit port is fluidly connected to the filling station; ii) the housing entry port is fluidly connected to the drug product preparer, and the housing exit port is fluidly connected to the filling station.
 11. The drug product filling device according to claim 10, comprising option i), wherein one or both of the housing entry port and the housing exit port are connected to a suction device.
 12. The drug product filling device according to claim 10, comprising option ii), wherein one or both of the fiber entry port and the fiber exit port are connected to a suction device.
 13. The drug product filling device according to claim 1, wherein the degasser has at least one entry port connected to the drug product preparer and at least one exit port connected to the filling station.
 14. A method of filling at least one liquid drug product into containers, comprising: A) providing at least one drug product filling device configured for filling at least one liquid drug product into containers, wherein step A) further comprises: i) providing a drug product preparer configured for preparing the liquid drug product; ii) providing a filling station configured for filling the liquid drug product into the containers, the filling station being fluidically coupled to the drug product preparer; iii) providing a degasser fluidly interposed between the drug product preparer and the filling station and the degasser comprising at least one membrane for separating off at least one gas from the liquid drug product; B) conducting the liquid drug product from the drug product preparer to the filling station, wherein the liquid drug product is at least partially degassed upon passing through the degasser; and C) filling the at least partially degassed liquid drug product into the containers using the filling station.
 15. The method according to claim 14, further comprising using the drug product filling device according to claim
 1. 16. A method of increasing the accuracy of the filling weight of a liquid drug product in a container, the method comprising: I. preparing the liquid drug product; II. degassing the liquid drug product by at least partially separating off at least one gas from the liquid drug product by using a degasser, the degasser comprising at least one membrane; III. filling the degassed liquid drug product into the container.
 17. A method of increasing the stability of at least one oxygen-sensitive active pharmaceutical ingredient in a liquid drug product, the method comprising: α. preparing the liquid drug product, the liquid drug product comprising at least one oxygen-sensitive active pharmaceutical ingredient; and β. degassing the liquid drug product by at least partially separating off at least one gas from the liquid drug product by using a degasser, the degasser comprising at least one membrane.
 18. A method of reducing polysorbate aggregate formation in a liquid drug product, the method comprising: X. preparing the liquid drug product, the liquid drug product comprising at least one oxygen-sensitive active pharmaceutical ingredient and at least one polysorbate; and Y. degassing the liquid drug product by at least partially separating off at least one gas from the liquid drug product by using a degasser, the degasser comprising at least one membrane. 